The goal of this project is to employ experimental animal models of autoimmune disease to examine disease mechanisms and potential therapies for disease such as multiple sclerosis (MS). Current work is focused on the acute and chronic-relapsing model, experimental allergic encephalomyelitis (EAE). This disease is induced by the transfer of lymphocytes sensitized to myelin antigens such as myelin basic protein, myelin oligodendrocyte glycoprotein, or proteolipid protein. Attention is focused on the role of activated T cells and the pathological and regulatory mechanism involved in lesion development. Previous studies have indicated that autoimmune disease is predominantly mediated by T cells that have a Th1 phenotype, meaning they make proinflammatory cytokines such as TNF and gamma interferon. Recent results from this project indicate that Th2 T cells which make regulatory cytokines such as IL4 and IL10 and thought to be beneficial can also mediate EAE. Th2 T cells have been shown to home to the CNS once they are activated. Furthermore, these Th2 T cells exacerbate disease induced by Th1 T cells. Thus, the Th1/Th2 paradigm which forms the basis of many current treatment trials in MS must be viewed with caution and care must be taken in applying these therapies. A component of this Th2-mediated worsening may be related to Th2 T cells recently demonstrated in this project that produce chemokines which are lymphokines that are responsible for recruiting inflammatory cells. To monitor the evolution of the EAE lesion, techniques have been developed to allow MR imaging of the mouse brain, initial studies indicate that MRI changes correlate with inflammation and demyelination. This technique will now be further developed to allow correlation of imaging parameters with immunological studies.